Apoptosis is one of the courses or manners of cell death proposed by Kerr, Wyllie, Currie et al. (see Brit. J. Cancer, 26, 239 (1972)). In embryology, there has been known cell death which occurs infallibly at a certain stage of embryogenesis at a certain place. This is also called "programmed cell death" to mean that it occurs according to the program of embryogenesis. Accordingly, it is morphologically differentiated from "necrosis" which is the course wherein necessary cells are injured to death. Morphological features of apoptosis include lack of contact with neighboring cells, concentration of cytoplasm, chromatin condensation and nucleus condensation which relate to endonuclease activity, and nucleus segmentation. Further, there are also observed disappearance of microvilli on the cell surface and planing of the cell surface (membrane blebbing). Moreover, fragmentation of DNA by endonuclease activity is also observed and cells form cellular fragments called apoptotic body, the resultant apoptotic body is rapidly and phagocytotically degraded by neighboring cells and macrophages. As a result, it is believed that apoptosis occurs.
It has been known that living bodies keep homeostasis by balancing cell growth with cell death. In the past, regulation of cell growth has been studied well but regulation of cell death has hardly been known. It has been known that apoptosis is induced by the lack of biologically active substances such as nerve growth factor (NGF) and colony stimulating factor (CSF), apoptosis inducing factor such as tumor necrosis factor (TNF), lymphotoxin, and gene products such as c-myc and p-53 (see Cell, 69, 119 (1992); Nature, 362,849 (1993)). It has also been known that apoptosis is inhibited by apoptosis inhibiting factor such as bcl-2 (see Nature, 359, 552 (1992); Nature, 359, 554 (1992)).
Recently, it has been recognized that apoptosis has important relation to various diseases and many trials have been made to induce or regulate cell apoptosis so as to diagnose, prevent and treat these diseases, to which attention has been drawn (see Science, 267,1456 (1995)).
Further, attention has also been drawn to the relation of apoptosis with hippocampal tardive nerve cell death in postischemic nerve cell death. Namely, when both side carotid arteries of Mongolian gerbil or rat are occluded for a short time (e.g., about 10 minutes) and then recanalized, cell death is observed in the both hippocampal CA1 region after two days (48 hours) and the cells are reduced after four days (96 hours) and vacuole is observed in dendrite, and disappear after one week.
The brain is a tissue in which oxygen consumption are highest in all the tissues and a place where a large amount of energy is consumed. Accordingly, the brain is weak against ischemia and is liable to undergo function disorder. Nerve cell death is markedly observed during embryogenesis and the cells constantly die after they are born. It is believed that about 100,000 nerve cells in human cerebral cortex will die a day. Nerve cells cannot regenerate. Accordingly, if the cells die to excess due to certain damage, function disorder will occur. Particularly, nerve cell death caused by ischemia, drugs, stress, or viruses is problematic. It becomes therefore much more important to elucidate the mechanism of the cell death so as to develop agents or methods for the treatment of neuronosis such as cerebral ischemia disorder or neuropathy due to AIDS, or to obtain a key to understand the long viability of the nerve cells.
Attention has also been drawn to the relation of apoptosis with neuro degenerative diseases such as Alzheimer's disease or Parkinson's disease, and it becomes more important to elucidate the mechanism of development of the diseases and to establish therapeutic methods or drugs for the treatment thereof.